Scientists from the University of Amsterdam (UvA) participating in an international study have discovered that a pair of lipoproteins that bind to outer cell membranes stimulate the activity of penicillin-binding proteins, which are known to be responsible for the synthesis of the protective cell wall (peptidoglycan layer) of bacteria. The findings open the door to the development of antibiotics that can inhibit interaction between penicillin-binding proteins and lipoproteins during bacterial cell growth. If successful, the implications would be huge, given that many bacteria have become resistant to the existing penicillins used to block penicillin-binding proteins. These findings were published in the 23 December 2010 issue of Cell.
Until recently, it was thought that synthesis of the peptidoglycan layer was regulated by proteins in the cytoplasmic membrane. However, the new study reveals it is actually the outer membrane that controls this process. The peptidoglycan layer within the bacterial cell wall determines a bacterium’s shape and protects it against mechanical and osmotic stress, and is itself produced by penicillin-binding proteins. By inhibiting that protein synthesis activity, penicillins (one of the largest classes of antibiotics) are able to kill the bacterium. Understanding how these lipoproteins function and are regulated will therefore provide a key to the development of new antibiotics.
The lipoproteins were discovered by researchers at the University of California in San Francisco (USA) and the Institute for Cell and Molecular Bioscience at Newcastle University (UK), who investigated the function of these proteins in close cooperation with molecular cell biologists at the UvA.
The molecular mechanism behind bacterial growth
The UvA team, led by Dr Tanneke den Blaauwen, was asked to determine the point in time and location at which the newly discovered lipoproteins were active and the conditions for their activity. With plenty of experience studying the activity of penicillin-binding proteins in cells, the team’s research work focuses on the molecular mechanism behind bacterial growth and division. By cultivating bacteria under precisely regulated conditions, they are able to determine the age of a bacterium based on its morphological features. Using florescent antibodies to visualise the distribution of proteins throughout a cell, microscopic recordings and careful image analysis of the fluorescent cells then make it possible to learn when proteins are active, whether that activity hinges on other proteins and where the proteins are situated within that cell.